Resveratrol Aspirinate Derivatives as Novel Chemopreventive Agents for Colon Cancer . The objective of this project is to develop resveratrol aspirinate derivatives as safe yet effective alternatives to aspirin for colon cancer prevention. Epidemiological studies have demonstrated that regular aspirin users are substantially less likely to develop CRC than non-users. However, the major limitation to the use of aspirin is its side effect to cause ulceration and bleeding in the gastrointestinal tract. In addition, the efficacy of aspirin is limited. Several innovative approaches have been employed in the last decade to address this issue. Nitric oxide (NO)-donating aspirin was one example. Unfortunately, a clinical chemoprevention trial of NO-aspirin for colon cancer was recently terminated prematurely due to concerns about its potential genotoxicity. Therefore, safer and more effective alternatives to aspirin are urgently needed. Our recent results show that resveratrol, a natural chemopreventive agent from grapes and berries, and its methylated derivatives can react with acetylsalicyloyl chloride to form resveratrol aspirinate (RAS) and related derivatives. Among all the synthesized derivatives, we found that RAS is the most active component and have much stronger growth inhibitory effect on human colon cancer cells (HCT-116 and HT-29) than resveratrol and aspirin along, as well as the combination of resveratrol and aspirin. In addition, we found that this type of compounds can be hydrolyzed to regenerate aspirin and related stilbene in mice and in human colon cancer cells. Therefore they may serve as prodrugs of aspirin and resveratrol and its derivatives. Based on our preliminary results, we hypothesize that RAS as a prodrug of aspirin and resveratrol is a more potent colon cancer preventive agent than aspirin and resveratrol. Compared to simply combining aspirin and resveratrol, RAS has not only greater growth inhibitory effects on human colon cancer cells, but also can prevent the damage of gastric epithelial cells caused by direct contact between aspirin and gastric mucosa. We plan to test our hypothesis in the following specific aims: 1. Determine the chemopreventive efficacy of resveratrol aspirinate (RAS) against aberrant crypt foci (ACF) formation in the azoxymethane-treated mouse model, as well as its long-term gastrointestinal side effects. 2. Study the bioavailability and biotransformation of resveratrol aspirinate (RAS) after administration of it to mice. We believe that results from this project will provide basic information on the chemopreventive effect of this novel agent on colon cancer. Since both aspirin and resveratrol have diverse pharmacologic activities, RAS will also be very useful for the prevention of other types of cancer and other diseases, such as inflammation, cardiovascular diseases, and diabetes. PUBLIC HEALTH RELEVANCE: Resveratrol Aspirinate Derivatives as Novel Chemopreventive Agents for Colon Cancer. Chemoprevention is an active cancer preventive strategy to inhibit or delay human carcinogenesis, using naturally occurring or synthetic chemical agents. Colorectal cancer (CRC) is a significant global health concern and is the third leading cause of death from cancer among both men and women worldwide (WHO statistics, 2009). Interest in the chemoprevention of CRC has increased significantly over the past fifteen years. An impressive body of evidence supports the notion that certain dietary phytochemicals and nonsteroidal anti- inflammatory drugs (NSAIDs) are promising agents for colon cancer prevention. The goal of the proposed research is to develop resveratrol aspirinate, a novel prodrug of aspirin and resveratrol, as a safe yet effective alternative to aspirin for colon cancer prevention.